CA2348167C - Pharmaceutical administration form for peptides, process for its preparation, and use - Google Patents

Abstract

The invention relates to pharmaceutical administration forms suitable for parenteral administration, which contains peptides prone to aggregation in the form of their acetate, gluconate, glucuronate, lactate, citrate, ascorbate, benzoate or phosphate salts in dissolved or dispersed form and additionally comprises one of the acids mentioned as free acid.

Description

Pharmaceutical Administration Form for Peptides, Process for Its Preparation, and Use Field of invention The invention relates to a novel pharmaceutical dosage form for the parenteral administration of peptides of the type which commonly tend to aggregate when dispersed or dissolved, particularly of LHRH analogs or LHRH antagonists and agonists, and processes for their preparation, and for their therapeutic use.

Background European patent No. 299,402 discloses the use of pharmaceutically active decapeptides such as SB-030, SB-075 (cetrorelix) and SB-088 in the form of their pharmaceutically acceptable, nontoxic acid addition salts such as hydrochlorides, hydrobromides, sulfates, phosphates, fumarates, gluconates, tannates, maleates, acetates, citrates, benzoates, succinates, alginates, pamoates, ascorbates, tartrates etc.

Japanese patent No. 6,321,800-A discloses a lyophilized peptide or protein preparation which contains gluconate salts as stabilizers. In one example, the solution contains 2.5% of magnesium gluconate, the active compounds described being, inter alia, vasopressin, LHRH and insulin.

It is known from the literature, such as from Powell, M.F., Pharmaceutical Research, 1258-1263(8) 1991; Dathe M. Int. J. Peptide Protein Res. 344-349(36) 1990, and Szejtli, J. Pharmaceutical Technology International 16-22, 1991, that oligopeptides, particularly those having a terminal acid amide function, are prone to forming of gels.
European patent No. 611,572 describes a process for preparing a lyophilizate of a peptide having 3-15 amino acids, according to which 100-10,000 parts by weight of the peptide are dissolved in acetic acid and treated with bulking agents such as mannitol, and then lyophilized to obtain a sterile-filtered lyophilizate of the peptide and to avoid gel formation.

German patent application No. 195 42 873 describes pharmaceutical dosage forms having a complicated composition, in the form of microparticles, according to which an ABA triblock copolymer is used, the A block of which is a polymer of milk and glycolic acid and the B polymer of which is a polyethylene glycol chain, together with an additive of one or more of serum proteins, polyamino acids, cyclodextrins, cyclodextrin derivatives, saccharides, amino sugars, amino acids, detergents and carboxylic acids. After inclusion of small or aggregation-sensitive amounts of polypeptide, these microparticles should also release the polypeptide continuously over a relatively long period.

East German patent No. 141,996 describes the preparation of pharmaceutical forms of native LHRH which are stable over a relatively long period and comply with the requirements for a preparation that can be parenterally administered . The key point here is the improvement in the shelf life of these preparations (page 2, lines 19-23).
No statement is made about the ability to filter the solutions. Buffer substances (also acetic acid) are also employed to improve the shelf life by establishing a range of pH 3.5 - 6.5.
The problem is not solved here of preparing sterile lyophilizates from gel-forming peptide salts.

European patent No. 175,506 treats an aqueous solution of the peptide with 1N acetic acid and then lyophilizes it to obtain the acetate salt of the peptide. The subject of this application is thus the synthesis of the peptide salts.

It has been shown, however, that in the case of the known acetate salts of the peptides prone to aggregation, such as the LHRH antagonists, the preparation of sterile solutions for parenteral administration by filtration, especially at high concentrations, is indeed possible, but aggregates can form shortly before injection after the dissolution of the lyophilizate. The aggregates then lead to a concentration-dependent lowering of the bioavailability from a peptide concentration of 0.5 mg/ml.

This problem occurs not only with injection solutions which are administered for the rapid release of the active compound, but is also observed with injection preparations which exhibit delayed release. Thus peptides, incorporated in matrices which should control the release of active compound, can have an undesirably low release on account of their being prone to aggregation. Thus the bioavailability is also lowered in this case.

Considering that the preferred route of administration of pharmaceutically active peptides such as LHRH agonists and antagonists, for example antarelix and cetrorelix, is the parenteral pharmaceutical form, a need was found to exist for the provision of stable injectable preparations having acceptable bioavailability, and which can be conveniently prepared, sterile-filtered and formulated. This applies in particular to injectable preparations in the form of reconstituted lyophilizates of soluble peptide salts and to microparticles, microcapsules or implants. This is all the more of importance considering of the more and more known varied areas of use of the LHRH antagonists.

A wider selection of parenterally, in particular subcutaneously, injectable, stable peptide solutions is desirable in view of the rapidly growing indications of this class of substances.

Brief description of the invention It is an object of the present invention to provide pharmaceutical dosage forms suitable for parenteral administration, which contain a peptide of the type commonly tending to aggregate when dissolved or dispersed. In accordance with the present invention the peptides are suitably present in the form of their acetate, gluconate, glucuronate, lactate, citrate, ascorbate, benzoate or phosphate salts, and these dosage forms can further contain anyone of the aforementioned compounds as the free acid, and optionally further additives and excipients such as acids, surfactents, polymers, lipids, and sugars.
Detailed description The dosage forms of the present invention can be present in dissolved or dispersed form in water or in aqueous solvent mixtures.

According to a further embodiment of the present invention, the dosage forms can also be present dissolved or dispersed in at least one pharmaceutically acceptable oil, suitably medium-chain triglycerides (neutral oils, such as sold under the trademark Miglyol) or castor oil, sesame oil, cottonseed oil, maize oil, peanut oil, and olive oil.
The peptides employed are the LHRH antagonists antide, A-75998, ganirelix and Nal-Glu antagonist, but in particular cetrorelix, antarelix and the antagonists according to US patent No. 5,942,493 and German patent No. 19,911,771.3.

Acid excipients are suitably gluconic acid, gllucuronic acid, galacturonic acid, glucaric acid, citric acid, ascorbic acid and amino acids.

By employing these compositions of the present invention, it is possible to suppress the aggregation of the peptide and thus to fulfil the requirements for a preparation having good bioavailability, which enriches the pharmaceutical armamentarium with efficient dosage composition technology.

It has been also, surprisingly, found that by the addition of gluconic, glucuronic, citric, lactic or ascorbic acid, the stability of various cetrorelix salts is considerably further improved.

According to the invention, the preparation and formulation of sterile-filtered, stable preparations is thus possible without any problems.

Suitably adding excipients such as acids, surfactents, polymers, lipids or sugars, the advantageous properties of the compositions of the present invention can be further improved. Such acids include gluconic acid, glucuronic acid, galacturonic acid, glucaric acid, lactic and citric acid, ascorbic acid and amino acids.
Surfactents can be suitably polyethylene glycol 12-(hydroxy)stearate (Solutol ), polyoxyethylene ricinoleate (Cremophor ), polysorbates, poloxamers, phospholipids, lecithins or benzalkonium chloride.

Suitable polymers are albumins, polyethylene glycols, cellulose derivatives, starch derivatives or polyvinylpyrrolidone. Examples of sugars include cyclodextrins and cyclodextrin derivatives. Chaotropic substances such as urea can also serve as additives and/or excipients.
The area of use of the preparations according to the present invention particularly include the prevention and therapy of all sex hormone-dependent conditions and diseases which can be influenced by LHRH analogs, i.e. L13RH agonists and LHRH
antagonists. Those to be particularly emphasized here include benign prostate hyperplasia, prostate cancer, precocious puberty, hirsutism, endometrial hyperplasia and its accompanying symptoms, endometrial carcinoma, in-vitro fertilization (IVF/COS/ART), contraception, premenstrual syndrome (PMS), uterine myomatosis, breast cancer, tubal obstruction (PTO), ovarian cancer, carcinoma of the uterus.

Particularly suitable compounds as LHRH antagonists are according to the invention cetrorelix, antarelix, antide, A-75998, ganirelix, the Nal-Glu antagonist, and LHRH
antagonists according to the US patent No. 5,942,493 and German patent No.
19,911,771.3.

The invention is further described with reference to the following examples.

Example 1 Aggregation investigations were carried out by polarization microscopy, on solutions of various cetrorelix salts without or with addition of excipients.

In polarized lighting a microscope with crossed polarizers, aggregated peptide solutions show images which are very similar to those of liquid-crystalline structures. In contrast, aggregate-free peptide solutions produce no such optical effects.

The following table shows the influence of a gluconic acid addition on the aggregation characteristics of cetrorelix acetate solutions.

Concentration of cetrorelix Gluconic acid in the pH Days without acetate, mg/ml reconstitution medium, %: aggregation 2.5 0 4.7 1 2.5 0.0071 4.5 2 2.5 0.071 3.7 2 2.5 0.71 3.1 12 Thus the addition of gluconic acid causes an improvement in the stability of cetrorelix acetate solutions by delaying or preventing aggregation.

Further experiments concentrated on cetrorelix gluconate without or with addition of gluconic acid. The most important results are summarized in the following table showing the aggregation characteristics of various solutions prepared from bulk cetrorelix gluconate.

Gluconic acid addition: Yes No Concentration of cetrorelix, pH Days without pH Days without mg/ml aggregation aggregation 2.5 3.0 >30 5 3.6 4 4.8 1 5 3.8 4 4.7 1 7.5 3.4 1 4.7 0 7.5 3.7 1 4.8 0 All these figures show that cetrorelix gluconate offers advantages in comparison to the acetate salt. Therefore, the addition of gluconic acid increases the shelf life of cetrorelix gluconate solutions.

Moreover, the stabilizing influence of glucuronic acid on cetrorelix acetate solutions and, as a further salt, also cetrorelix glucuronate, was tested for its aggregation behavior, as summarized in the following table by illustrating the aggregation characteristics of various concentrated solutions of cetrorelix acetate and cetrorelix glucuronate without or with addition of glucuronic acid.

Glucuronic acid Yes No addition:
Salt form Concentration of pH Days without pH Days without cetrorelix, mg/ml aggregation. aggregation Acetate 2.5 3.0 >21 4.7 0 Acetate 5 3.0 0 Glucuronate 2.5 2.9 >30 4.5 3 Glucuronate 5 2.7 >30 4.6 0 Also the replacement of the acetate salt by a glucuronate salt, significantly improved the aggregation stability of cetrorelix similarly to that with the gluconate salt. By the addition of glucuronic acid to cetrorelix glucuronate solutions, the aggregation stability of these solutions can be even further improved.

The aggregation-free duration in days of cetrorelix acetate solutions is shown in the following table after the addition of 10% of a-cyclod.extrin, 20% of hydroxypropyl-(3-cyclodextrin, or 20% of y-cyclodextrin.

Concentration of L-Cyclo-dextrin Hydroxypropyl-j3-cyclodextrin y-Cyclodextrin cetrorelix acetate, mg/ml 2.5 7 24 98 + (168, 182, 189) 0 7 31 + (140, 147, 182) 7.5 0 10 5 + (20, 20, 20) 0 2 2 +(4,4,4) By the addition of hydroxypropyl-(3-cyclodextrin and particularly of y-cyclodextrin, the aggregation stability of cetrorelix acetate solutions can be significantly further improved.

The aggregation-free duration in days of 2.5 mg/ml cetrorelix gluconate solutions is shown in the following table after the addition of a-cyclodextrin, hydroxypropyl-(3-cyclodextrin or y-cyclodextrin.

Cyclodextrin type Concentration of cyclodextrin, % Days without aggregation y-Cyclodextrin 20 182 6.8 126 Hydroxypropyl-(3- 20 189 cyclodextrin 6.8 91 a-Cyclodextrin 10 140 10 By the addition of hydroxypropyl-o-cyclodextrin or of y-cyclodextrin, the aggregation stability of cetrorelix gluconate solutions can also be significantly improved.

The aggregation-free duration in days of cetrorelix acetate solutions is shown in the following table with the addition of polyvinylpyrrolidone sold under the trademark Kollidon 12 PF or 17 PF.

Concentration of Concentration of Days without aggregation Days without aggregation cetrorelix, mg/ml Kollidon , % with Kollidon 12 PF with Kollidon 17 PF

2.5 0 0 0 5 By the addition of various types of polyvinylpyrrolidone, the aggregation stability of cetrorelix acetate solutions can also be significantly improved.
The aggregation behavior of cetrorelix acetate solutions is shown in the following table with the addition of various excipients assessed by polarization microscopy and according to the optical appearance.

Excipient Conc. of Conc. of Aggregation Appearance excipient cetrorelix (microscopy) Solutol HS 15 5.00% 2.5 mg/ml yes, after 14 clear days solution 10.00% 2.5 mg/ml >_ 12 days clear without solution aggregation 20.00% 2.5 mg/ml >_ 12 days clear without solution aggregation Cremophor EL 5.00% 2.5 mg/ml yes, after 10 clear days solution 10.00% 2.5 mg/ml >_ 12 days clear without solution aggregation 20.00% 2.5 mg/ml >_ 12 days clear without solution aggregation 20.00% 5 mg/ml yes, after 1 day clear, viscose L-glutamic acid 0.80% 2.5 mg/ml yes, after 2 clear days solution, pH 3.8 Glucaric 2.50% 2.5 mg/ml 12 days clear acid without solution, aggregation pH 2.5 Galact- 2.50% 2.5 mg/ml >_ 12 days clear uronic acid without solution, aggregation pH 2.6 Example 2 Cetrorelix bulk material is dissolved at a concentration of 10 mg/ml in 30%
acetic acid and diluted with an aqueous solution of the additives to a final concentration of 1 mg/ml of peptide in 3% acetic acid. This solution is then sterile-filtered and lyophilized (5 mg per vial).

After reconstitution of these lyophilizates, the solutions (2.5 mg/ml of cetrorelix) are investgated in the following tests for aggregate formation and release behavior:

are investgated in the following tests for aggregate formation and release behavior:
= Polarized microscope (pol. mic.): days without aggregation.

= Filterability in %:

= Cetrorelix solutions are prepared according to a standardized procedure and filtered through 0.22 m or 0.45 gm filters by centrifugation. The concentration of cetrorelix in the filtrate is determined by HPLC and indicated as a % value, based on the starting concentration before filtration (filterability in %).

= In-vitro release form (RRS, release in Ringer's solution) with the %
released after 1 hour and after 6 hours.

The in-vitro release behavior is determined at 37 C in a flow procedure using Ringer's solution as medium. The concentration measurement is carried out by HPLC.
Cetrorelix samples, corresponding to 10 mg of cetrorelix base, are weighed into the flow cell, mixed with 4 ml water and stirred for 10 min. After addition of 6 ml of Ringer's solution to the sample, Ringer's solution is pumped uniformly through the flow cell at a flow rate of 0.5 ml/min, with stirring.

= Rat animal experiment is carried out with cetrorelix residual content in the muscle in %
of the administered dose 168 hours after injection.

Some prepared batches of cetrorelix acetate lyophilizate and the corresponding test results of 2.5 mg/ml cetrorelix acetate solutions are shown in the following table.
Batches of cetrorelix acetate Pol.mic., days 0.22 m RRS, [%] Rat % i.m.
lyophilizate (5 mg)... without aggr. filterable after after Excipients [%] 1 h 6 h 168 h only mannitol (= control) 0 about 55 Solutol/mannitol 48 100 Cremophor/mannitol 46 101 Solutol/alanine 16 98 17 24 Solutol/alanine/ gluconic acid 19 101 57 68 5.7 Cremophor/mannitol/ gluconic >45 101 acid Solutol/tryptophan/ mannitol imposs.
Solutol/tryptophan/ gluconic 6 9.6 acid Cyclodextrin molar 2 101 16 27 10 ratio 1:10/mannitol Cyclodextrin molar >45 102 68 74 ratio 1:10/mannitol/ gluconic acid Cyclodextrin molar 17 100 68 76 ratio 1:30/mannitol Cyclodextrin molar 5 101 39 52 6.3 ratio 1: 1 0/alanine/gluconic acid Mannitol/citric acid 1 102 45 53 Solutol/mannitol/ citric acid >36 100 84 91 7.4 Solutol/alanine/ citric acid 1 99 47 54 Solutol/glycine >36 97 24 31 Solutol/urea 21 100 32 40 Solutol/glycine/ gluconic acid >36 99 82 89 Solutol/urea/gluconic acid >36 100 Cremophor/alanine/ gluconic (36) acid Cremophor/urea/ gluconic acid (36) Pluronic F127/mannitol 1 5% Tween 80/mannitol >16 Polyethylene glycol 1 4000/mannitol Dextran/mannitol 1 Phenylmercury acetate/mannitol2 From the foregoing table it is evident that with a large number of the tested excipients from various groups of substances (surfactant acids, amino acids, polymers, sugars, sugar alcohols, cyclodextrins, preservatives), stabilizing effects can be achieved in vitro (polarized microscope, filterability, in-vitro release) and in vivo individually or with mixtures of these excipients. This reduced tendency to aggregate and thus improved in-vitro release of active compound also leads in the rat experiment to improved bioavailabilities of the peptide active compound and thus to reduced residual contents in the rat muscle.
Further in-vitro and in-vivo data of batches containing various cetrorelix salts without or with addition of stabilizing excipients are listed in the following table.
Cetrorelix salts (reconstituted Concentr. of Pol. mic days RRS, [%] Rat % i.m.
with water) cetrorelix from lyo with-out after after aggr.
Excipients mg/ml 1 h 6 h 168 h Acetate 2.5 0 12 24.5 about 55 Acetate 2.5 0 13 35.9 about 55 Acetate 5 0 10 35 Acetate reconstituted with 2.5 18 50 63.2 15.2 gluconic acid Acetate + Kollidon 12 PF 2.5 84 15 43.4 20.2 Acetate + Kollidon 17 PF 2.5 98 22 50.6 Acetate + benzalkonium 2.5 6.3 30.3 chloride Acetate + 2.5 7.3 23.3 phospholipids Acetate + y-cyclodextrin 2.5 22.6 44.5 10 (1:10) Acetate + y-cyclodextrin 2.5 28 56.7 (1:30) Acetate + y-cyclodextrin 2.5 35.1 56.6 (1:50) Acetate + y-cyclodextrin 2.5 >168 34.5 60.2 3.6 (1:90) Acetate + y-cyclodextrin 5 140 19 47.8 (1:90) Acetate + y-cyclodextrin 7.5 20 (1:90) Acetate + y-cyclodextrin 10 4 45.2 (1:90) Acetate reconstituted with 15 49.1 gluconic acid Gluconate 2.5 18 45.3 Gluconate 2.5 11.3 46 Gluconate reconstituted with 2.5 77.5 83.6 gluconic acid Citrate 15 9 20.3 Lactate bulk 20 55.2 Embonate 15 13 43 Example 3 Cetrorelix formulations which are slower and less prone to aggregate (with better filterability and polarized microscope results) and exhibit more rapid in-vitro release in Ringer's solution precipitate after 168 hours in the rat muscle experiment due to their lower residual cetrorelix content. Therefore, a higher bioavailability is expected of such formulations.
Some results of rat muscle experiments have already been listed in the last preceding tables.
In the further rat muscle experiments shown in the following table, in addition to the residual content in the muscle, the cetrorelix content in the plasma was also determined.
With the aid of these data, the stabilizing influence of the excipients tested is even more clear.
PMoreover, it was possible by the replacement of the acetate salt with other cetrorelix salt forms to achieve an improved bioavailability and yet better reduced residual amount in the rat muscle experiment.

Substance Dose Cetrorelix Cetrorelix content Cetrorelix content (cetrorelix) (mg/kg) concentration of in the muscle in the plasma, % of the inj.soln (168 h), % of the the dose (mg/ml) dose Acetate + Solutol + 1.5 2.5 5.7 alanine + gluconic acid Acetate +Solutol + 1.5 2.5 9.6 tryptophan + gluconic acid Acetate + cyclo- 1.5 2.5 10.0 83.4 dextrin 1:10 Acetate + cyclo- 1.5 2.5 6.3 81.8 dextrin 1:10, alanine, gluconic acid Acetate + 1.5 2.5 3.8 Solutol +
gluconic acid Acetate + 1.5 2.5 7.4 Solutol +
citric acid Acetate 1.5 3 55.1 92.2 Acetate in 1.5 3 22.3 74.2 Miglyol Acetate + 1.5 3 76.9 39.8 benzalkonium chloride Acetate + 20% 1.5 3 3.6 106.2 cyclodextrin Acetate + 20% 1.5 3 20.2 88.4 Kollidon Acetate + 1.5 3 23.6 106.1 glucuronic acid Acetate + 1.5 3 15.2 95.5 gluconic acid Acetate + 20% 3.0 10 45.2 60.9 cyclodextrin Acetate 3.0 15 56.5 28.7 Acetate in 3.0 15 24.2 57.2 Miglyol Acetate + 0.025% 3.0 15 10.5 21.4 benzalkon.
Acetate + 3.0 15 78.1 43.8 glucuronic acid Acetate + 3.0 15 49.1 45.5 gluconic acid Gluconate 1.5 15 37.9 46.9 Gluconate in 1.5 3 24.6 58.0 mannitol Gluconate in 1.5 3 25.4 75.2 mannitol Gluconate in 1.5 3 28.8 46.3 Miglyol Gluconate in gluconic 1.5 3 13.2 120.0 acid Gluconate in 3.0 15 29.2 gluconic acid Gluconate in 3.0 15 43.5 74.2 gluconic acid Glucuronate 1.5 3 16.5 78.6 Glucuronate 3.0 15 18.8 Lactate 3.0 15 33.2 72.1 Lactate 1.5 3 30.7 67.1 Citrate lyo/a 1.5 3 22.8 36.6 Citrate in Miglyol 1.5 3 14.8 53.1 Base 1.5 3 27.2 122.2 Base in Miglyol 1.5 3 38.9 55.9 Benzoate in 1.5 3 34.2 32.7 mannitol Benzoate in 1.5 3 33.1 21.1 Miglyol Phosphate 1.5 3 32.9 22.6

Claims (17)

1. Pharmaceutical administration form for parenteral administration, comprising:
(a) a peptidic lutenizing hormone-releasing hormone (LHRH) antagonist salt, wherein the peptidic LHRH antagonist salt is the LHRH antagonist cetrorelix acetate in a concentration of 2.5 mg/ml total solution;

(b) a pharmaceutically acceptable acid and percent in total solution thereof, selected from the group consisting of gluconic acid of at least 0.0071%, glucaric acid of at least 2.5% and galaturonic acid of at least 2.5%, wherein the pharmaceutically acceptable acid is present as free acid and is in an amount capable of imparting a pH between 2.5 to 4.5 to the composition and suppressing aggregation of the peptidic LHRH antagonist salt; and (c) a carrier, wherein the carrier is water or an aqueous solvent mixture.

2. Pharmaceutical administration form of claim 1, further comprising an excipient.

3. Pharmaceutical administration form according to claim 2, wherein the excipient comprises gluconic acid, glucuronic acid, galaturonic acid, glucaric acid, citric acid, ascorbic acid or an amino acid.

4. Pharmaceutical administration form according to claim 2, wherein the excipient comprises polyethylene glycol 12-(hydroxy)stearate (Solutol®), polyoxyethylene ricinoleate (Cremophor®), polysorbates, poloxamers, phospholipids, lecithins or a preservative.

5. Pharmaceutical administration form according to claim 2, wherein the excipient comprises albumins, polyethylene glycols, cellulose derivatives, starch derivatives or polyvinylpyrollidone.

6. Pharmaceutical administration form according to claim 2, wherein the excipient comprises cyclodextrin or its derivatives, or sugar alcohols.

7. Pharmaceutical administration form according to claim 2, wherein the excipient comprises urea or other chaotropic substances.

8. Pharmaceutical administration form according to claim 1, wherein the release of the peptidic LHRH antagonist salt is delayed by the use of a polymer.

9. Process for the production of a pharmaceutical administration form according to claim 1 or 2, characterized in that, by double decomposition of peptide salts with gluconic acid, glucaric acid or galaturonic acid, the corresponding salts are prepared in a stoichiometric ratio, dissolved in water for injection, mixed with excipients according to any one of claims 3 to 7, then sterile-filtered.

10. Process for the production of a pharmaceutical administration form according to claim 1 or 2, characterized in that, by double decomposition of peptide salts with gluconic acid, glucaric acid or galacturonic acid, the corresponding salts are prepared in a stoichiometrie ratio, these salts are incorporated into delayed-release microparticles of homo- or copolymers of lactic and glycolic acid and these microparticles are suspended in a physiologically tolerable medium for injection.

11. Use of the pharmaceutical administration form according to claim 1 for parenteral administration in sex hormone-dependent, benign and malignant diseases.

12. Use of the pharmaceutical compositions according to claim 1 for parenteral administration in sex hormone- dependent, benign and malignant diseases, benign prostate hyperplasia, carcinoma of the prostate, precocious puberty, hirsutism, endometrial hyperplasia and its accompanying symptoms, endometrial carcinoma, in-vitro fertilization (IVF/COS/ART), contraception, premenstrual syndrome (PMS), uterine myomatosis, breast cancer, tubal obstruction (PTO), ovarian cancer and carcinoma of the uterus.

13. Pharmaceutical administration form of claim 8, wherein the polymer is a homo- or copolymer of lactic or glycolic acid.

14. Pharmaceutical administration form of claim 4, wherein the preservative is benzalkonium chloride or phenylmercury acetate.

15. Pharmaceutical administration form of claim 6, wherein the sugar alcohol is mannitol.

16. Pharmaceutical administration form of claim 1, wherein the pharmaceutical administration form for parenteral administration form is an injection preparation.

17. Pharmaceutical administration form of claim 16, wherein the injection preparation is for subcutaneous injection.